T Cell Anergy

Capable Caspase

Science Signaling  19 Aug 2008:
Vol. 1, Issue 33, pp. ec296
DOI: 10.1126/scisignal.133ec296

T cell anergy is a state of unresponsiveness that is induced by suboptimal activation of T cells; namely, engagement of the T cell receptor (TCR) in the absence of a costimulating signal, such as stimulation of CD28. Anergic T cells do not proliferate in response to further stimulation, making the induction of anergy an effective method for inactivating self-reactive T cells. Stimulation of the TCR results in the Ca2+-dependent transcription of genes encoding proteins associated with anergy. The group of Puga et al. had previously shown that one of these proteins was the proapoptotic protein caspase-3. In the current study, the authors mixed mouse T cells expressing an ovalbumin-specific TCR with Chinese hamster ovary (CHO) cells expressing a complex of MHC class II and ovalbumin peptide (CHO-OVA) to induce T cell anergy. The abundances of Casp3 mRNA and active caspase-3 protein were increased in these T cells compared with those of T cells mixed with non-OVA CHO cells; however, the anergic T cells did not exhibit any of the characteristics of apoptotic cells. When T cells and CHO-OVA cells were incubated with a caspase inhibitor, proliferation assays showed that the T cells did not become anergic. Similarly, Casp3–/– T cells were less susceptible than cells from wild-type mice to becoming anergic after TCR stimulation in vitro. Western blotting assays showed that caspase-3 was recruited to the plasma membrane of anergic T cells, where it cleaved the adaptor protein GADS and the guanine nucleotide exchange factor Vav1, both of which are TCR signaling components. Together, these data suggest a nonapoptotic role for caspase-3 in maintaining the hyporesponsiveness of anergic T cells by inhibiting TCR signaling.

I. Puga, A. Rao, F. Macian, Targeted cleavage of signaling proteins by caspase 3 inhibits T cell receptor signaling in anergic T cells. Immunity 29, 193-204 (2008). [PubMed]